Joint inflammation, or spondyloarthritis (SpA), is a common extra-intestinal manifestation of inflammatory bowel disease (IBD) and associated with changes in the gut microbiome. Sulfasalazine is a prodrug known to be effective for the treatment of inflammatory bowel disease (IBD)-associated peripheral spondyloarthritis (pSpA), but the mechanistic role for the gut microbiome in regulating its clinical efficacy is not well understood. To evaluate the possibility that sulfasalazine targeting of gut bacterial metabolism can impact IBD SpA, we analyzed longitudinal data from IBD SpA patients treated with sulfasalazine compared to standard of care controls. Microbiome analysis of 22 IBD-pSpA subjects treated with sulfasalazine revealed a SpA responder baseline microbiome enriched in Faecalibacterium prausnitzii and the capacity for butyrate production. The ability of bacterial taxa markers to discriminate between responders and non-respnoders was validated in a separate IBD-SpA cohort (n=16). In vitro, we show that sulfapyridine promotes butyrate production and transcription of the butyryl-CoA:acetate CoA-transferase (called but) in F. prausnitzii. Consistent with sulfapyridine antagonism dihydropteroate synthase, excess folate blocked sulfasalazine induction of but. Gut metabolomic analysis revealed evidence of a folate trap (in which thymine is consumed by the salvage pathway leading to the accumulation of deoxyuridine) only in subjects with clinical response. In mouse models, sulfasalazine therapy enhanced fecal butyrate production which limited colitis in SPF and gnotobiotic mice colonized with responder microbiomes. In contrast, gnotobiotic mice colonized with non-responder microbiomes did not increase butyrate production when treated with sulfasalazine. The addition of F. prausnitzii to non-responder colonized mice was sufficient to restore enhanced sulfasalazine protection from colitis. These findings reveal a mechanistic link between the efficacy of sulfasalazine therapy and the function of the gut microbiome with the potential to guide diagnostic and therapeutic approaches for IBD-pSpA.

Grace Maldarelli

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